Role of the Lineage Gene Phox2B in Neuroblastoma Development

by Alam, Goleeta N.

The oncogene MYCN is amplified in a subset of unfavorable neuroblastomas that consist of predominantly undifferentiated neuroblasts. We used the MYCN transgenic mice - an animal model for the human disease, to examine the cellular basis of neuroblastoma development. These mice develop overt neuroblastomas preceded by a pre-neoplastic stage characterized by development of hyperplastic lesions in the sympathetic ganglia during the first week after birth. We show that both hyperplastic lesions as well as primary tumors are composed of highly proliferating cells that express Phox2B. MYCN promotes the proliferation of these Phox2B+ neuronal progenitors and arrests their differentiation, thereby leading to an expansion of this population. A minor population of undifferentiated cells expressing the neural stem cell marker, nestin, was also identified in both the hyperplastic lesions and primary tumors implicating these cells as possible precursors to the proliferating Phox2B+ neuronal progenitors. Immunoblot analysis of a panel of human neuroblastoma cells showed Phox2B expression in a majority of cells examined which was downregulated significantly upon retinoic acid-induced neuronal differentiation, implicating a role for Phox2B in maintenance of the neuroblastic phenotype. Interestingly, Phox2B knockdown in the bipotent BE(2)-C neuroblastoma cell line resulted in shift towards a glial fate while in the SK-N-AS cells Phox2B downregulation resulted in decreased survival. Given together, these data support the notion that Phox2B may function as a lineage-survival oncogene in an aberrant developmental context, leading to neuroblastoma development.